The overall goal of this research is to continue to characterize the toxic effects of methamphetamine (MA) and related drugs on a biochemical, morphological, and behavioral basis. MA, amphetamine (AMPH), methylenedioxyamphetamine (MDMA) and a number of related drugs are widely abused and are neurotoxic when used in high and/or repeatedly administered doses. Cocaine is another drug of abuse which has long-lasting effects after repeated administration. The extent, duration, and consequences of this toxicity are important to understanding and treating the consequences of these drugs of abuse. The purpose of this research is to extend what is known about the relatively short-term toxicity of these drugs to an investigation of the long-term toxicity and consequences of this toxicity. To achieve the goals of this research, we will determine the magnitude of the long-lasting toxic effects of MA, AMPH, and MDMA upon dopamine (DA) and 5-hydroxytryptamine (5HT) systems as a function of dose and drug-free time period. We will measure the amine levels, the number of high affinity uptake sites, changes in local glucose utilization and alterations in morphology as lone as 64 weeks after the drug has been discontinued. We will also test MA analogues such as N-ethylamphetamine and dimethylamphetamine to determine whether these analogues have toxic potential. Further, we have recently found that a long-term effect of repeated exposure to COC is an alteration of dopamine receptors in the brain. We do not know the extent, duration or consequences of this alteration. We will examine these parameters by determining the effects on receptor subtypes of repeated administration of cocaine, MA and toxic analogues. The long-term consequence of receptor modifications may be correlated with neurotoxicity and/or with behavioral changes that may result from repeated administration of these compounds. We will also investigate the behavioral consequences of drug-induced neurotoxicity. If behavior is altered by neurotoxic drugs or by drug challenge, it will suggest that there are direct behavioral consequences, or that function of particular neuronal systems are compromised by this drug-induced damage. These experiments will be crucial in predicting and treating the consequences of the ingestion of neurotoxic drugs commonly abused by humans.